Does sleep improve memory organization?
Takeuchi Masashi,Furuta Hisakazu,Sumiyoshi Tomiki,Suzuki Michio,Ochiai Yoko,Hosokawa Munehito,Matsui Mie,Kurachi Masayoshi
Frontiers in behavioral neuroscience
Sleep can integrate information into existing memory networks, look for common patterns and distil overarching rules, or simply stabilize and strengthen the memory exactly as it was learned. Recent research has shown that sleep facilitates abstraction of gist information as well as integration across multiple memories, insight into hidden solutions, and even the ability to make creative connections between distantly related ideas and concepts. To investigate the effect of sleep on memory organization, 35 normal volunteers were randomly assigned either to the sleep (n = 17) or wake group (n = 18). The sleep subjects performed the Japanese Verbal Learning Test (JVLT), a measure of learning and memory, three times in the evening, and slept. On the following morning (9 h later), they were asked to recall the words on the list. The wake subjects took the same test in the morning, and were asked to recall the words in the same time interval as in the sleep group. The semantic clustering ratio (SCR), divided by the total number of words recalled, was used as an index of memory organization. Our main interest was whether the sleep subjects elicit a greater increase in this measure from the third to the fourth assessments. Time × Group interaction effect on SCR was not significant between the sleep group and wake group as a whole. Meanwhile, the change in the SCR between the third and fourth trials was negatively correlated with duration of nocturnal waking in the sleep group, but not other sleep indices. Based on this observation, further analysis was conducted for subjects in the sleep group who awoke nocturnally for <60 min for comparison with the wake group. A significant Time × Group interaction was noted; these "good-sleepers" showed a significantly greater improvement in the memory index compared with the wake subjects. These results provide the first suggestion that sleep may enhance memory organization, which requires further study.
10.3389/fnbeh.2014.00065
Time of day accounts for overnight improvement in sequence learning.
Keisler Aysha,Ashe James,Willingham Daniel T
Learning & memory (Cold Spring Harbor, N.Y.)
The theory that certain skills improve with a night of sleep has received considerable interest in recent years. However, because sleep typically occurs at the same time of day in humans, it is difficult to separate the effects of sleep from those of time of day. By using a version of the Serial Response Time Task, we assessed the role of sleep in implicit sequence learning while controlling for possible time-of-day effects. We replicated the apparent benefit of sleep on human participants. However, our data show that sleep does not affect implicit sequence learning; rather, time of day affects the ability of participants to express what they have learned.
10.1101/lm.751807
Cognitive Impairment After Sleep Deprivation Rescued by Transcranial Magnetic Stimulation Application in Octodon degus.
Estrada C,López D,Conesa A,Fernández-Gómez F J,Gonzalez-Cuello A,Toledo F,Tunez I,Blin O,Bordet R,Richardson J C,Fernandez-Villalba E,Herrero M T
Neurotoxicity research
Sleep is indispensable for maintaining regular daily life activities and is of fundamental physiological importance for cognitive performance. Sleep deprivation (SD) may affect learning capacity and the ability to form new memories, particularly with regard to hippocampus-dependent tasks. Transcranial magnetic stimulation (TMS) is a non-invasive procedure of electromagnetic induction that generates electric currents, activating nearby nerve cells in the stimulated cortical area. Several studies have looked into the potential therapeutic use of TMS. The present study was designed to evaluate how TMS could improve learning and memory functions following SD in Octodon degus. Thirty juvenile (18 months old) females were divided into three groups (control, acute, and chronic TMS treatment-with and without SD). TMS-treated groups were placed in plastic cylindrical cages designed to keep them immobile, while receiving head magnetic stimulation. SD was achieved by gently handling the animals to keep them awake during the night. Behavioral tests included radial arm maze (RAM), Barnes maze (BM), and novel object recognition. When TMS treatment was applied over several days, there was significant improvement of cognitive performance after SD, with no side effects. A single TMS session reduced the number of errors for the RAM test and improved latency and reduced errors for the BM test, which both evaluate spatial memory. Moreover, chronic TMS treatment brings about a significant improvement in both spatial and working memories.
10.1007/s12640-015-9544-x
Sleep loss, learning capacity and academic performance.
Curcio Giuseppe,Ferrara Michele,De Gennaro Luigi
Sleep medicine reviews
At a time when several studies have highlighted the relationship between sleep, learning and memory processes, an in-depth analysis of the effects of sleep deprivation on student learning ability and academic performance would appear to be essential. Most studies have been naturalistic correlative investigations, where sleep schedules were correlated with school and academic achievement. Nonetheless, some authors were able to actively manipulate sleep in order to observe neurocognitive and behavioral consequences, such as learning, memory capacity and school performance. The findings strongly suggest that: (a) students of different education levels (from school to university) are chronically sleep deprived or suffer from poor sleep quality and consequent daytime sleepiness; (b) sleep quality and quantity are closely related to student learning capacity and academic performance; (c) sleep loss is frequently associated with poor declarative and procedural learning in students; (d) studies in which sleep was actively restricted or optimized showed, respectively, a worsening and an improvement in neurocognitive and academic performance. These results may been related to the specific involvement of the prefrontal cortex (PFC) in vulnerability to sleep loss. Most methodological limitations are discussed and some future research goals are suggested.
10.1016/j.smrv.2005.11.001
Evidence for two distinct sleep-related long-term memory consolidation processes.
Schönauer Monika,Grätsch Melanie,Gais Steffen
Cortex; a journal devoted to the study of the nervous system and behavior
Numerous studies examine the effect of a night's sleep on memory consolidation, but few go beyond this short time-scale to test long-lasting effects of sleep on memory. We investigated long-term effects of sleep on typical memory tasks. During the hours following learning, participants slept or stayed awake. We compared recall performance between wake and sleep conditions after delays of up to 6 days. Performance develops in two distinct ways. Word pair, syllable, and motor sequence learning tasks benefit from sleep during the first day after encoding, when compared with daytime or nighttime wakefulness. However, performance in the wake conditions recovers after another night of sleep, so that we observe no lasting effect of sleep. Sleep deprivation before recall does not impair performance. Thus, fatigue cannot adequately explain the lack of long-term effects. We suggest that the hippocampus might serve as a buffer during the retention interval, and consolidation occurs during delayed sleep. In contrast, a non-hippocampal mirror-tracing task benefits significantly from sleep, even when tested after a 4-day delay including recovery sleep. This indicates a dissociation between two sleep-related consolidation mechanisms, which could rely on distinct neuronal processes.
10.1016/j.cortex.2014.08.005
Sleep-dependent facilitation of episodic memory details.
van der Helm Els,Gujar Ninad,Nishida Masaki,Walker Matthew P
PloS one
While a role for sleep in declarative memory processing is established, the qualitative nature of this consolidation benefit, and the physiological mechanisms mediating it, remain debated. Here, we investigate the impact of sleep physiology on characteristics of episodic memory using an item- (memory elements) and context- (contextual details associated with those elements) learning paradigm; the latter being especially dependent on the hippocampus. Following back-to-back encoding of two word lists, each associated with a different context, participants were assigned to either a Nap-group, who obtained a 120-min nap, or a No Nap-group. Six hours post-encoding, participants performed a recognition test involving item-memory and context-memory judgments. In contrast to item-memory, which demonstrated no between-group differences, a significant benefit in context-memory developed in the Nap-group, the extent of which correlated both with the amount of stage-2 NREM sleep and frontal fast sleep-spindles. Furthermore, a difference was observed on the basis of word-list order, with the sleep benefit and associated physiological correlations being selective for the second word-list, learned last (most proximal to sleep). These findings suggest that sleep may preferentially benefit contextual (hippocampal-dependent) aspects of memory, supported by sleep-spindle oscillations, and that the temporal order of initial learning differentially determines subsequent offline consolidation.
10.1371/journal.pone.0027421
Assembly-Specific Disruption of Hippocampal Replay Leads to Selective Memory Deficit.
Gridchyn Igor,Schoenenberger Philipp,O'Neill Joseph,Csicsvari Jozsef
Neuron
Memory consolidation is thought to depend on the reactivation of waking hippocampal firing patterns during sleep. Following goal learning, the reactivation of place cell firing can represent goals and predicts subsequent memory recall. However, it is unclear whether reactivation promotes the recall of the reactivated memories only or triggers wider reorganization. We trained animals to locate goals at fixed locations in two different environments. Following learning, by performing online assembly content decoding, the reactivation of only one environment was disrupted, leading to recall deficit in that environment. The place map of the disrupted environment was destabilized but re-emerged once the goal was relearned. These data demonstrate that sleep reactivation facilitates goal-memory retrieval by strengthening memories that enable the selection of context-specific hippocampal maps. However, sleep reactivation may not be needed for the stabilization of place maps considering that the map of the disrupted environment re-emerged after the retraining of goals.
10.1016/j.neuron.2020.01.021
Sleep restores place learning to the adenylyl cyclase mutant .
Journal of neurogenetics
Sleep plays an important role in regulating plasticity. In , the relationship between sleep and learning and memory has primarily focused on mushroom body dependent operant-learning assays such as aversive phototaxic suppression and courtship conditioning. In this study, sleep was increased in the classic mutant () and () by feeding them the GABA-A agonist gaboxadol (Gab). Performance was evaluated in each mutant in response to social enrichment and place learning, tasks that do not require the mushroom body. Gab-induced sleep did not restore behavioral plasticity to either or mutants following social enrichment. However, increased sleep restored place learning to mutants. These data extend the positive effects of enhanced sleep to place learning and highlight the utility of Gab for elucidating the beneficial effects of sleep on brain functioning.
10.1080/01677063.2020.1720674
Sleep and neurocognitive decline in the Hispanic Community Health Study/Study of Latinos.
Ramos Alberto R,Tarraf Wassim,Wu Benson,Redline Susan,Cai Jianwen,Daviglus Martha L,Gallo Linda,Mossavar-Rahmani Yasmin,Perreira Krista M,Zee Phyllis,Zeng Donglin,Gonzalez Hector M
Alzheimer's & dementia : the journal of the Alzheimer's Association
INTRODUCTION:To determine if sleep-disordered breathing (SDB), daytime sleepiness, insomnia, and sleep duration predict seven-year neurocognitive decline in US Hispanics/Latinos (N = 5247). METHODS:The exposures were baseline SDB, daytime sleepiness, insomnia, and sleep duration. The outcomes were change in episodic learning and memory (B-SEVLT-Sum and SEVLT-Recall), language (word fluency [WF]), processing speed (Digit Symbol Substitution), and a cognitive impairment screener (Six-item Screener [SIS]). RESULTS:Mean age was 63 ± 8 years, with 55% of the population being female with 7.0% Central American, 24.5% Cuban, 9.3% Dominican, 35.9% Mexican, 14.4% Puerto Rican, and 5.1% South American background. Long sleep (>9 hours), but not short sleep (<6 hours), was associated with decline (standard deviation units) in episodic learning and memory (β -0.22 [se = 0.06]; P < .001; β = -0.13 [se = 0.06]; P < .05), WF (Pwf = -0.20 [se 5 0.06]; P < .01), and SIS (β = -0.16 [se = 0.06]; P < .01), but not processing speed, after adjusting for covariates. SDB, sleepiness, and insomnia were not associated with neurocognitive decline. CONCLUSION:Long sleep duration predicted seven-year cognitive decline.
10.1016/j.jalz.2019.08.191
Thalamo-Cortical White Matter Underlies Motor Memory Consolidation via Modulation of Sleep Spindles in Young and Older Adults.
Vien Catherine,Boré Arnaud,Boutin Arnaud,Pinsard Basile,Carrier Julie,Doyon Julien,Fogel Stuart
Neuroscience
Ample evidence suggests that consolidation of the memory trace associated with a newly acquired motor sequence is supported by thalamo-cortical spindle activity during subsequent sleep, as well as functional changes in a distributed cortico-striatal network. To date, however, no studies have investigated whether the structural white matter connections between these regions affect motor sequence memory consolidation in relation with sleep spindles. Here, we used diffusion weighted imaging (DWI) tractography to reconstruct the major fascicles of the cortico-striato-pallido-thalamo-cortical loop in both young and older participants who were trained on an explicit finger sequence learning task before and after a daytime nap. Thereby, this allowed us to examine whether post-learning sleep spindles measured using polysomnographic recordings interact with consolidation processes and this specific neural network. Our findings provide evidence corroborating the critical role of NREM2 thalamo-cortical sleep spindles in motor sequence memory consolidation, and show that the post-learning changes in these neurophysiological events relate specifically to white matter characteristics in thalamo-cortical fascicles. Moreover, we demonstrate that microstructure along this fascicle relates indirectly to offline gains in performance through an increase of spindle density over motor-related cortical areas. These results suggest that the integrity of thalamo-cortical projections, via their impact on sleep spindle generation, may represent one of the critical mechanisms modulating the expression of sleep-dependent offline gains following motor sequence learning in healthy adults.
10.1016/j.neuroscience.2018.12.049
How odor cues help to optimize learning during sleep in a real life-setting.
Neumann Franziska,Oberhauser Vitus,Kornmeier Jürgen
Scientific reports
Effortless learning during sleep is everybody's dream. Several studies found that presenting odor cues during learning and selectively during slow wave sleep increases learning success. The current study extends previous research in three aspects to test for optimization and practical applicability of this cueing effect: We (1) performed a field study of vocabulary-learning in a regular school setting, (2) stimulated with odor cues during the whole night without sleep monitoring, and (3) applied the odor additionally as retrieval cue in a subsequent test. We found an odor cueing effect with comparable effect sizes (d between 0.6 and 1.2) as studies with sleep monitoring and selective cueing. Further, we observed some (non-significant) indication for a further performance benefit with additional cueing during the recall test. Our results replicate previous findings and provide important extensions: First, the odor effect also works outside the lab. Second, continuous cueing at night produces similar effect sizes as a study with selective cueing in specific sleep stages. Whether odor cueing during memory recall further increases memory performance hast to be shown in future studies. Overall, our results extend the knowledge on odor cueing effects and provide a realistic practical perspective on it.
10.1038/s41598-020-57613-7
The relationship between subjective sleep quality and cognitive performance in healthy young adults: Evidence from three empirical studies.
Zavecz Zsófia,Nagy Tamás,Galkó Adrienn,Nemeth Dezso,Janacsek Karolina
Scientific reports
The role of subjective sleep quality in cognitive performance has gained increasing attention in recent decades. In this paper, our aim was to test the relationship between subjective sleep quality and a wide range of cognitive functions in a healthy young adult sample combined across three studies. Sleep quality was assessed by the Pittsburgh Sleep Quality Index, the Athens Insomnia Scale, and a sleep diary to capture general subjective sleep quality, and the Groningen Sleep Quality Scale to capture prior night's sleep quality. Within cognitive functions, we tested working memory, executive functions, and several sub-processes of procedural learning. To provide more reliable results, we included robust frequentist as well as Bayesian statistical analyses. Unequivocally across all analyses, we showed that there is no association between subjective sleep quality and cognitive performance in the domains of working memory, executive functions and procedural learning in healthy young adults. Our paper can contribute to a deeper understanding of subjective sleep quality and its measures, and we discuss various factors that may affect whether associations can be observed between subjective sleep quality and cognitive performance.
10.1038/s41598-020-61627-6
Aqueous Leaf Extract of Withania somnifera as a Potential Neuroprotective Agent in Sleep-deprived Rats: a Mechanistic Study.
Manchanda Shaffi,Mishra Rachana,Singh Rumani,Kaur Taranjeet,Kaur Gurcharan
Molecular neurobiology
Modern lifestyle and sustained stress of professional commitments in the current societal set up often disrupts the normal sleep cycle and duration which is known to lead to cognitive impairments. In the present study, we report whether leaf extract of Withania somnifera (Ashwagandha) has potential neuroprotective role in acute stress of sleep deprivation. Experiments were performed on three groups of adult Wistar rats: group 1 (vehicle treated-undisturbed sleep [VUD]), group 2 (vehicle treated-sleep deprived [VSD]), and group 3 (ASH-WEX treated-sleep deprived [WSD]). Groups 1 and 2 received single oral feeding of vehicle and group 3 received ASH-WEX orally (140 mg/kg or 1 ml/250 g of body weight) for 15 consecutive days. Immediately after this regimen, animals from group 1 were allowed undisturbed sleep (between 6 a.m. and 6 p.m.), whereas rats of groups 2 and 3 were deprived of sleep during this period. We observed that WSD rats showed significant improvement in their performance in behavioral tests as compared to VSD group. At the molecular level, VSD rats showed acute change in the expression of proteins involved in synaptic plasticity, cell survival, and apoptosis in the hippocampus region of brain, which was suppressed by ASH-WEX treatment thus indicating decreased cellular stress and apoptosis in WSD group. This data suggest that Ashwagandha may be a potential agent to suppress the acute effects of sleep loss on learning and memory impairments and may emerge as a novel supplement to control SD-induced cognitive impairments.
10.1007/s12035-016-9883-5
Metformin pretreatment enhanced learning and memory in cerebral forebrain ischaemia: the role of the AMPK/BDNF/P70SK signalling pathway.
Ghadernezhad Negar,Khalaj Leila,Pazoki-Toroudi Hamidreza,Mirmasoumi Masoumeh,Ashabi Ghorbangol
Pharmaceutical biology
Context Metformin induced AMP-activated protein kinase (AMPK) and protected neurons in cerebral ischaemia. Objective This study examined pretreatment with metformin and activation of AMPK in molecular and behavioral levels associated with memory. Materials and methods Rats were pretreated with metformin (200 mg/kg) for 2 weeks and 4-vessels occlusion global cerebral ischaemia was induced. Three days after ischaemia, memory improvement was done by passive avoidance task and neurological scores were evaluated. The amount of Brain-Derived Neurotropic Factor (BDNF) and phosphorylated and total P70S6 kinase (P70S6K) were measured. Results Pretreatment with metformin (met) in the met + ischaemia/reperfusion (I/R) group reduced latency time for enter to dark chamber compared with the sham group (p < 0.001) and increased latency time compared with the I/R group (p < 0.001). Injection of Compound C (CC) (as an AMPK inhibitor) concomitant with metformin reduced latency time in I/R rats compared with the I/R + met group (p < 0.05). Neurological scores were reduced in met treated rats compared with the sham group. Pretreatment with metformin in I/R animals reduced levels of pro-BDNF compared with the I/R group (p < 0.001) but increased that compared with the sham group (p < 0.001). The level of pro-BDNF decreased in the met + CC + I/R group compared with the met + I/R group (p < 0.01). Pretreatment with metformin in I/R animals significantly increased P70S6K compared with the I/R group (p < 0.001). Conclusion Short-term memory in ischaemic rats treated with metformin increased step-through latency; sensory-motor evaluation was applied and a group of ischaemia rats that were pretreated with metformin showed high levels of BDNF, P70S6K that seemed to be due to increasing AMPK.
10.3109/13880209.2016.1150306
Short-term sleep deprivation stimulates hippocampal neurogenesis in rats following global cerebral ischemia/reperfusion.
Cheng Oumei,Li Rong,Zhao Lei,Yu Lijuan,Yang Bin,Wang Jia,Chen Beibei,Yang Junqing
PloS one
BACKGROUND:Sleep deprivation (SD) plays a complex role in central nervous system (CNS) diseases. Recent studies indicate that short-term SD can affect the extent of ischemic damage. The aim of this study was to investigate whether short-term SD could stimulate hippocampal neurogenesis in a rat model of global cerebral ischemia/reperfusion (GCIR). METHODS:One hundred Sprague-Dawley rats were randomly divided into Sham, GCIR and short-term SD groups based on different durations of SD; the short-term SD group was randomly divided into three subgroups: the GCIR+6hSD*3d-treated, GCIR+12hSD-treated and GCIR+12hSD*3d-treated groups. The GCIR rat model was induced via the bilateral occlusion of the common carotid arteries and hemorrhagic hypotension. The rats were sleep-deprived starting at 48 h following GCIR. A Morris water maze test was used to assess learning and memory ability; cell proliferation and differentiation were analyzed via 5-bromodeoxyuridine (BrdU) and neuron-specific enolase (NSE), respectively, at 14 and 28 d; the expression of hippocampal BDNF was measured after 7 d. RESULTS:The different durations of short-term SD designed in our experiment exhibited improvement in cognitive function as well as increased hippocampal BDNF expression. Additionally, the short-term SD groups also showed an increased number of BrdU- and BrdU/NSE-positive cells compared with the GCIR group. Of the three short-term SD groups, the GCIR+12hSD*3d-treated group experienced the most substantial beneficial effects. CONCLUSIONS:Short-term SD, especially the GCIR+12hSD*3d-treated method, stimulates neurogenesis in the hippocampal dentate gyrus (DG) of rats that undergo GCIR, and BDNF may be an underlying mechanism in this process.
10.1371/journal.pone.0125877
Combined citicoline and docosahexaenoic acid treatment improves cognitive dysfunction following transient brain ischemia.
Nakazaki Eri,Yabuki Yasushi,Izumi Hisanao,Shinoda Yasuharu,Watanabe Fumiko,Hishida Yukihiro,Kamimura Ayako,Fukunaga Kohji
Journal of pharmacological sciences
Phospholipids are structural components of cellular membranes that play important roles as precursors for various signaling pathways in modulating neuronal membrane function and maintenance of the intracellular environment. Phosphatidylcholine (PtdCho) is the most abundant cellular phospholipid. Citicoline and docosahexaenoic acid (DHA) are essential intermediates in the synthesis of PtdCho. Both PtdCho intermediates have independently shown neuroprotective effects in cerebral ischemia, but their combined effect is unknown. This study aimed to investigate the combined effect of oral citicoline and DHA treatment on improvement of cognitive deficits following cerebral ischemia using a 20-min bilateral common carotid artery occlusion (BCCAO) mouse model. BCCAO ischemic mice were treated for a total of 11 days with a combination of citicoline (40 mg/kg body weight/day) and DHA (300 mg/kg body weight/day) or each alone. Combined citicoline and DHA synergistically and significantly improved learning and memory ability of ischemic mice compared with either alone. Further, citicoline and DHA treatment significantly prevented neuronal cell death, and slightly increased DHA-containing PtdCho in the hippocampus, albeit not significantly. Taken together, these findings suggest that combined citicoline and DHA treatment may have synergistic benefits for partially improving memory deficits following transient brain ischemia.
10.1016/j.jphs.2019.02.003
Improvement of cognitive deficit and neuronal damage in rats with chronic cerebral ischemia via relative long-term inhibition of rho-kinase.
Huang Lin,He Zhi,Guo Lianjun,Wang Hongxing
Cellular and molecular neurobiology
(1) The role of activation of Rho-kinase in the pathogenesis of cognitive deficit and neuronal damage caused by chronic global ischemia is not clear. In this study, hydroxyfasudil, a Rho-kinase inhibitor, was found to improve the learning and memory performance significantly in rats with ischemia induced by chronic cerebral hypoperfusion after permanent bilateral carotid artery ligation (BCAL). This was observed by the administration of hydroxyfasudil (1 mg/kg or 10 mg/kg, once per day for 30 days) to ischemic rats and the measurements of escape latency and time spent in the target quadrant among the ischemic, sham, and ischemic plus hydroxyfasudil rats by the method of Morris water maze. (2) In electrophysiological study, hydroxyfasudil abolished the inhibition of long-term potentiation (LTP) in rats with ischemia. Morphologically, it also markedly reduced pathological changes such as neuronal cells loss and nuclei shrinkage in cortex and hippocampus of ischemic rats. Biochemical analysis showed that the inhibition of Rho-kinase by hydroxyfasudil reduced the amount of MDA and increased the activities of SOD and GPx in ischemic rats that had increased MDA and decreased SOD and GPx activities. (3) To explore mechanism (s) of the beneficial effects of hydroxyfasudil in ischemia, we performed immunohistochemistry and RT-PCR analyses of NMDA NR2B subunit and for the first time found that hydroxyfasudil increased the expression of NR2B in cortex and hippocampus at both protein and mRNA levels. (4) Taken together, our data further support the notion that the inhibition of Rho-kinase provides neuroprotective effects in cerebral ischemia.
10.1007/s10571-007-9157-x
PPARα Agonist Fenofibrate Ameliorates Learning and Memory Deficits in Rats Following Global Cerebral Ischemia.
Xuan Ai-Guo,Chen Yan,Long Da-Hong,Zhang Meng,Ji Wei-Dong,Zhang Wen-Juan,Liu Ji-Hong,Hong Le-Peng,He Xiao-Song,Chen Wen-Liang
Molecular neurobiology
Increasing evidence demonstrates that local inflammation contributes to neuronal death following cerebral ischemia. Peroxisome proliferator-activated receptor α (PPARα) activation has been reported to exhibit many pharmacological effects including anti-inflammatory functions. The aim of this study was to investigate the neuroprotective effects of PPARα agonist fenofibrate on the behavioral dysfunction induced by global cerebral ischemia/reperfusion (GCI/R) injury in rats. The present study showed that fenofibrate treatment significantly reduced hippocampal neuronal death, and improved memory impairment and hippocampal neurogenesis after GCI/R. Fenofibrate administration also inhibited GCI/R-induced over-activation of microglia but not astrocytes and prevented up-regulations of pro-inflammatory mediators in hippocampus. Further study demonstrated that treatment with fenofibrate suppressed GCI/R-induced activations of P65 NF-κB and P38 MAPK. Our data suggest that the PPARα agonist fenofibrate can exert functional recovery of memory deficits and neuroprotective effect against GCI/R in rats via triggering of neurogenesis and anti-inflammatory effect mediated by inhibiting activation of P65 NF-κB and P38 MAPK in the hippocampus, which can contribute to improvement in neurological deficits.
10.1007/s12035-014-8882-7
Neuroprotective and Functional Improvement Effects of Methylene Blue in Global Cerebral Ischemia.
Lu Qing,Tucker Donovan,Dong Yan,Zhao Ningjun,Zhang Quanguang
Molecular neurobiology
Transient global cerebral ischemia (GCI) causes delayed neuronal cell death in the vulnerable hippocampus CA1 subfield, as well as behavioral deficits. Ischemia reperfusion (I/R) produces excessive reactive oxygen species and plays a key role in brain injury. The mitochondrial electron respiratory chain is the main cellular source of free radical generation, and dysfunction of mitochondria has a significant impact on the neuronal cell death in ischemic brain. The aim of the present study is to investigate the potential beneficial effects of methylene blue (MB) in a four-vessel occlusion (4VO) GCI model on adult male rats. MB was delivered at a dose of 0.5 mg/kg/day for 7 days, through a mini-pump implanted subcutaneously after GCI. We first found that MB significantly improved ischemic neuronal survival in the hippocampal CA1 region as measured by cresyl violet staining as well as NeuN staining. We also found that MB has the ability to rescue ischemia-induced decreases of cytochrome c oxidase activity and ATP generation in the CA1 region following I/R. Further analysis with labeling of MitoTracker® Red revealed that the depolarization of mitochondrial membrane potential (MMP) was markedly attenuated following MB treatment. In addition, the induction of caspase-3, caspase-8, and caspase-9 activities and the increased numbers of TUNEL-positive cells of the CA1 region were significantly reduced by MB application. Correspondingly, Barnes maze tests showed that the deterioration of spatial learning and memory performance following GCI was significantly improved in the MB-treatment group compared to the ischemic control group. In summary, our study suggests that MB may be a promising therapeutic agent targeting neuronal cell death and cognitive deficits following transient global cerebral ischemia.
10.1007/s12035-015-9455-0
Levodopa improves learning and memory ability on global cerebral ischemia-reperfusion injured rats in the Morris water maze test.
Wang Wenzhu,Liu Lixu,Jiang Peng,Chen Chen,Zhang Tong
Neuroscience letters
Previous studies have shown that levodopa (L-dopa) for 1-7days improved the consciousness level of certain patients who suffered from ischemia-reperfusion injury and were comatose for a long time period after cerebral resuscitation treatment. It also has an awakening effect on patients with disorders of consciousness. This study aimed to investigate whether L-dopa, which is used clinically to treat Parkinson's disease, might also ameliorate the behavior of rats following global cerebral ischemia-reperfusion injury. Fifty-six healthy adult male Sprague-Dawley rats were randomly divided into four groups: shamoperated, global cerebral ischemia mode, 25mg/kg/d L-dopa intervention, and 50mg/kg/d L-dopa intervention. The level of consciousness and modified neurological severity score (NSS) of the rats in each group were measured before reperfusion and 6, 24, and 72h and 1-4 weeks after reperfusion. The Morris water maze test was used to assess behavior of rats 1 week after reperfusion and 2 weeks after reperfusion in each group. The results showed that after global cerebral ischemiareperfusion injury, neurological deficits of rats are severe, and space exploration capacity and learning and memory capacity are significantly decreased. L-dopa can shorten the duration of coma in rats following global cerebral ischemia-reperfusion injury and improve the symptoms of neurological deficits and advanced learning and memory. In the range of the selected doses, the relationship between L-dopa and improvement of the neurological behavior in rats was not dose-dependent. Dopamine may be useful for treating severe ischemia-reperfusion brain injury.
10.1016/j.neulet.2016.11.026
Improving memory: a role for phosphodiesterases.
Blokland A,Schreiber R,Prickaerts J
Current pharmaceutical design
During the last decennia, our understanding of the neurobiological processes underlying learning and memory has continuously improved, leading to the identification of targets for the development of memory-enhancing drugs. Here we review a class of drugs which has more recently been identified: the phosphodiesterase (PDE) inhibitors. An overview is given of the different PDEs that are known and we focus on three PDEs which have been identified as possible relevant targets for memory improvement: PDE2, PDE4 and PDE5. PDEs differ in the substrate, i.e. cyclic adenosine monophosphate (cAMP) and/or cyclic guanosine monophosphate (cGMP), being hydrolyzed. Since these cyclic nucleotides have been suggested to play distinct roles in processes of memory, selective PDE inhibitors preventing the breakdown of cAMP and/or cGMP could improve memory. The present data suggest that PDE4 (cAMP) is involved in acquisition processes, although a possible role in late consolidation processes cannot be excluded. PDE5 (cGMP) is involved in early consolidation processes. Since PDE2 inhibition affects both cAMP and cGMP, PDE2 inhibitors may improve both memory processes. The field of PDEs is highly dynamic and new isoforms of PDEs are still being described. This may lead to the discovery and development of new memory enhancing drugs that selectively inhibit such isoforms. Such drugs may exert their effects only in specific brain areas and hence possess an improved side effect profile.
Is caffeine a cognitive enhancer?
Nehlig Astrid
Journal of Alzheimer's disease : JAD
The effects of caffeine on cognition were reviewed based on the large body of literature available on the topic. Caffeine does not usually affect performance in learning and memory tasks, although caffeine may occasionally have facilitatory or inhibitory effects on memory and learning. Caffeine facilitates learning in tasks in which information is presented passively; in tasks in which material is learned intentionally, caffeine has no effect. Caffeine facilitates performance in tasks involving working memory to a limited extent, but hinders performance in tasks that heavily depend on working memory, and caffeine appears to rather improve memory performance under suboptimal alertness conditions. Most studies, however, found improvements in reaction time. The ingestion of caffeine does not seem to affect long-term memory. At low doses, caffeine improves hedonic tone and reduces anxiety, while at high doses, there is an increase in tense arousal, including anxiety, nervousness, jitteriness. The larger improvement of performance in fatigued subjects confirms that caffeine is a mild stimulant. Caffeine has also been reported to prevent cognitive decline in healthy subjects but the results of the studies are heterogeneous, some finding no age-related effect while others reported effects only in one sex and mainly in the oldest population. In conclusion, it appears that caffeine cannot be considered a ;pure' cognitive enhancer. Its indirect action on arousal, mood and concentration contributes in large part to its cognitive enhancing properties.
10.3233/JAD-2010-091315
Lipids and cognition.
Morley John E,Banks William A
Journal of Alzheimer's disease : JAD
Cholesterol, omega-3 fatty acids, and triglycerides have been postulated to play roles in affecting cognition in Alzheimer's disease (AD), the elderly, and obesity. Animal, human epidemiological, and in vitro studies each suggest an important role for cholesterol in the regulation of amyloid-beta (Abeta) protein and the pathogenesis of AD. In contrast, well controlled studies have failed to show an effect of cholesterol lowering with statins on cognition, indicating that the cholesterol effect is spurious or indirect, possibly mediated through other lipids. Administration of diedocosahexanoic acid (DHA), a dietary omega-3 fatty acid derived primarily from fish and plants, improves cognition and reduces lipid peroxidation in animals, including in mouse models of AD. DHA also blocks Abeta-mediated tau phosphorylation. In humans, fish consumption or administration of DHA has been associated with cognitive improvement in many, but not all, studies. Both human and animal studies show that obesity is associated with cognitive impairments and that lowering triglycerides improves cognition. Administration of triglycerides to mice decreases learning and memory and impairs long-term potential. The effect of triglycerides may be mediated in part by inducing resistance to positive cognitive features of gastrointestinal hormones such as leptin. Overall, these studies strongly suggest that some lipids affect cognition in AD, the elderly, and obesity through a variety of mechanisms yet to be fully defined.
10.3233/JAD-2010-091576
The co-agonist site of NMDA-glutamate receptors: a novel therapeutic target for age-related cognitive decline.
Panizzutti Rogerio,Scoriels Linda,Avellar Marcos
Current pharmaceutical design
The world population is growing older and age-related cognitive decline is becoming a burden of societal importance. D-serine is an endogenous amino acid that activates the co-agonist site of the NMDA-glutamate receptor, which is related to cognitive functions, such as learning and memory. Studies in aged rodents have shown a marked decrease in the levels of D-serine in brain regions such as the hippocampus, a key region for encoding memory. Exogenous administration of D-serine in rodents has demonstrated pro-cognitive effects in several brain functions, including memory and executive function. Further to animal studies, our group has observed an agerelated decrease in D-serine in the blood of healthy adults and elderly. The oral administration of D-serine induced significant improvement in executive function and spatial problem solving in elderly, some of the key cognitive domains affected by aging. In this review we propose the activation of the co-agonist site of NMDA receptors as a target to remediate features of the age-related cognitive decline. The cognitive effects of other agents targeting the co-agonist site of NMDA receptors are also discussed.
Can physical exercise in old age improve memory and hippocampal function?
Brain : a journal of neurology
Physical exercise can convey a protective effect against cognitive decline in ageing and Alzheimer's disease. While the long-term health-promoting and protective effects of exercise are encouraging, it's potential to induce neuronal and vascular plasticity in the ageing brain is still poorly understood. It remains unclear whether exercise slows the trajectory of normal ageing by modifying vascular and metabolic risk factors and/or consistently boosts brain function by inducing structural and neurochemical changes in the hippocampus and related medial temporal lobe circuitry-brain areas that are important for learning and memory. Hence, it remains to be established to what extent exercise interventions in old age can improve brain plasticity above and beyond preservation of function. Existing data suggest that exercise trials aiming for improvement and preservation may require different outcome measures and that the balance between the two may depend on exercise intensity and duration, the presence of preclinical Alzheimer's disease pathology, vascular and metabolic risk factors and genetic variability.
10.1093/brain/awv407
Aging, synaptic dysfunction, and insulin-like growth factor (IGF)-1.
The journals of gerontology. Series A, Biological sciences and medical sciences
Insulin-like growth factor (IGF)-1 is an important neurotrophic hormone. Deficiency of this hormone has been reported to influence the genesis of cognitive impairment and dementia in the elderly patients. Nevertheless, there are studies indicating that cognitive function can be maintained into old age even in the absence of circulating IGF-1 and studies that link IGF-1 to an acceleration of neurological diseases. Although IGF-1 has a complex role in brain function, synaptic effects appear to be central to the IGF-1-induced improvement in learning and memory. In this review, synaptic mechanisms of learning and memory and the effects of IGF-1 on synaptic communication are discussed. The emerging data indicate that synaptic function decreases with age and that IGF-1 contributes to information processing in the brain. Further studies that detail the specific actions of this important neurotrophic hormone will likely lead to therapies that result in improved cognitive function for the elderly patients.
10.1093/gerona/gls118
Photobiomodulation for traumatic brain injury and stroke.
Hamblin Michael R
Journal of neuroscience research
There is a notable lack of therapeutic alternatives for what is fast becoming a global epidemic of traumatic brain injury (TBI). Photobiomodulation (PBM) employs red or near-infrared (NIR) light (600-1100nm) to stimulate healing, protect tissue from dying, increase mitochondrial function, improve blood flow, and tissue oxygenation. PBM can also act to reduce swelling, increase antioxidants, decrease inflammation, protect against apoptosis, and modulate microglial activation state. All these mechanisms of action strongly suggest that PBM delivered to the head should be beneficial in cases of both acute and chronic TBI. Most reports have used NIR light either from lasers or from light-emitting diodes (LEDs). Many studies in small animal models of acute TBI have found positive effects on neurological function, learning and memory, and reduced inflammation and cell death in the brain. There is evidence that PBM can help the brain repair itself by stimulating neurogenesis, upregulating BDNF synthesis, and encouraging synaptogenesis. In healthy human volunteers (including students and healthy elderly women), PBM has been shown to increase regional cerebral blood flow, tissue oxygenation, and improve memory, mood, and cognitive function. Clinical studies have been conducted in patients suffering from the chronic effects of TBI. There have been reports showing improvement in executive function, working memory, and sleep. Functional magnetic resonance imaging has shown modulation of activation in intrinsic brain networks likely to be damaged in TBI (default mode network and salience network).
10.1002/jnr.24190
Glucagon-Like Peptide-1: A Focus on Neurodegenerative Diseases.
Grieco Maddalena,Giorgi Alessandra,Gentile Maria Cristina,d'Erme Maria,Morano Susanna,Maras Bruno,Filardi Tiziana
Frontiers in neuroscience
Diabetes mellitus is one of the major risk factors for cognitive dysfunction. The pathogenesis of brain impairment caused by chronic hyperglycemia is complex and includes mitochondrial dysfunction, neuroinflammation, neurotransmitters' alteration, and vascular disease, which lead to cognitive impairment, neurodegeneration, loss of synaptic plasticity, brain aging, and dementia. Glucagon-like peptide-1 (GLP-1), a gut released hormone, is attracting attention as a possible link between metabolic and brain impairment. Several studies have shown the influence of GPL-1 on neuronal functions such as thermogenesis, blood pressure control, neurogenesis, neurodegeneration, retinal repair, and energy homeostasis. Moreover, modulation of GLP-1 activity can influence amyloid β peptide aggregation in Alzheimer's disease (AD) and dopamine (DA) levels in Parkinson's disease (PD). GLP-1 receptor agonists (GLP-1RAs) showed beneficial actions on brain ischemia in animal models, such as the reduction of cerebral infarct area and the improvement of neurological deficit, acting mainly through inhibition of oxidative stress, inflammation, and apoptosis. They might also exert a beneficial effect on the cognitive impairment induced by diabetes or obesity improving learning and memory by modulating synaptic plasticity. Moreover, GLP-1RAs reduced hippocampal neurodegeneration. Besides this, there are growing evidences on neuroprotective effects of these agonists in animal models of neurodegenerative diseases, regardless of diabetes. In PD animal models, GPL-1RAs were able to protect motor activity and dopaminergic neurons whereas in AD models, they seemed to improve nearly all neuropathological features and cognitive functions. Although further clinical studies of GPL-1RAs in humans are needed, they seem to be a promising therapy for diabetes-associated cognitive decline.
10.3389/fnins.2019.01112
A novel neuroregenerative approach using ET(B) receptor agonist, IRL-1620, to treat CNS disorders.
Gulati A,Hornick M G,Briyal S,Lavhale M S
Physiological research
Endothelin B (ET(B)) receptors present in abundance the central nervous system (CNS) have been shown to have significant implications in its development and neurogenesis. We have targeted ET(B) receptors stimulation using a highly specific agonist, IRL-1620, to treat CNS disorders. In a rat model of cerebral ischemia intravenous administration IRL-1620 significantly reduced infarct volume and improved neurological and motor functions compared to control. This improvement, in part, is due to an increase in neuroregeneration. We also investigated the role of IRL-1620 in animal models of Alzheimer's disease (AD). IRL-1620 improved learning and memory, reduced oxidative stress and increased VEGF and NGF in Abeta treated rats. IRL-1620 also improved learning and memory in an aged APP/PS1 transgenic mouse model of AD. These promising findings prompted us to initiate human studies. Successful chemistry, manufacturing and control along with mice, rat and dog toxicological studies led to completion of a human Phase I study in healthy volunteers. We found that a dose of 0.6 microg/kg of IRL-1620 can be safely administered, three times every four hours, without any adverse effect. A Phase II clinical study with IRL-1620 has been initiated in patients with cerebral ischemia and mild to moderate AD.
10.33549/physiolres.933859
Epigenetic modifications in the nervous system and their impact upon cognitive impairments.
Rudenko Andrii,Tsai Li-Huei
Neuropharmacology
Epigenetic regulation has been long considered to be a critical mechanism in the control of key aspects of cellular functions such as cell division, growth, and cell fate determination. Exciting recent developments have demonstrated that epigenetic mechanisms can also play necessary roles in the nervous system by regulating, for example, neuronal gene expression, DNA damage, and genome stability. Despite the fact that postmitotic neurons are developmentally less active then dividing cells, epigenetic regulation appears to provide means of both long-lasting and very dynamic regulation of neuronal function. Growing evidence indicates that epigenetic mechanisms in the central nervous system (CNS) are important for regulating not only specific aspects of individual neuronal metabolism but also for maintaining function of neuronal circuits and regulating their behavioral outputs. Multiple reports demonstrated that higher-level cognitive behaviors, such as learning and memory, are subject to a sophisticated epigenetic control, which includes interplay between multiple mechanisms of neuronal chromatin modification. Experiments with animal models have demonstrated that various epigenetic manipulations can affect cognition in different ways, from severe dysfunction to substantial improvement. In humans, epigenetic dysregulation has been known to underlie a number of disorders that are accompanied by mental impairment. Here, we review some of the epigenetic mechanisms that regulate cognition and how their disruption may contribute to cognitive dysfunctions. Due to the fact that histone acetylation and DNA methylation are some of the best-studied and critically important epigenomic modifications our research team has particularly strong expertise in, in this review, we are going to concentrate on histone acetylation, as well as DNA methylation/hydroxymethylation, in the mammalian CNS. Additional epigenetic modifications, not surveyed here, are being discussed in depth in the other review articles in this issue of Neuropharmacology.
10.1016/j.neuropharm.2014.01.043
Promising therapeutics with natural bioactive compounds for improving learning and memory--a review of randomized trials.
Kumar Hemant,More Sandeep Vasant,Han Sang-Don,Choi Jin-Yong,Choi Dong-Kug
Molecules (Basel, Switzerland)
Cognitive disorders can be associated with brain trauma, neurodegenerative disease or as a part of physiological aging. Aging in humans is generally associated with deterioration of cognitive performance and, in particular, learning and memory. Different therapeutic approaches are available to treat cognitive impairment during physiological aging and neurodegenerative or psychiatric disorders. Traditional herbal medicine and numerous plants, either directly as supplements or indirectly in the form of food, improve brain functions including memory and attention. More than a hundred herbal medicinal plants have been traditionally used for learning and memory improvement, but only a few have been tested in randomized clinical trials. Here, we will enumerate those medicinal plants that show positive effects on various cognitive functions in learning and memory clinical trials. Moreover, besides natural products that show promising effects in clinical trials, we briefly discuss medicinal plants that have promising experimental data or initial clinical data and might have potential to reach a clinical trial in the near future.
10.3390/molecules170910503
Physical exercise, neuroplasticity, spatial learning and memory.
Cassilhas Ricardo C,Tufik Sergio,de Mello Marco Túlio
Cellular and molecular life sciences : CMLS
There has long been discussion regarding the positive effects of physical exercise on brain activity. However, physical exercise has only recently begun to receive the attention of the scientific community, with major interest in its effects on the cognitive functions, spatial learning and memory, as a non-drug method of maintaining brain health and treating neurodegenerative and/or psychiatric conditions. In humans, several studies have shown the beneficial effects of aerobic and resistance exercises in adult and geriatric populations. More recently, studies employing animal models have attempted to elucidate the mechanisms underlying neuroplasticity related to physical exercise-induced spatial learning and memory improvement, even under neurodegenerative conditions. In an attempt to clarify these issues, the present review aims to discuss the role of physical exercise in the improvement of spatial learning and memory and the cellular and molecular mechanisms involved in neuroplasticity.
10.1007/s00018-015-2102-0